Women account for nearly one-half of new HIV-1 infections worldwide, including the majority of infections in Africa. Heterosexual intercourse is responsible for most HIV-1 transmissions to women, and the majority of HIV-1 infected women are of reproductive age. Biologic and epidemiological studies have suggested that the use of hormonal contraception may influence HIV-1 susceptibility and infectiousness, but the relationship has not been consistent across all studies. Understanding the relationship between hormonal contraceptive use and HIV-1 risk is a topic of public health importance, because effective family planning is central to initiatives to improve the health of women and children worldwide. A central critique of studies of the hormonal contraception-HIV-1 relationship has been that condom use, particularly accurate reporting of use, could differ for contraceptive users versus non-users, a bias that could result in increased HIV-1 risk. Pre-exposure prophylaxis (PrEP), in which HIV-1 uninfected persons use antiretrovirals to protect against sexual HIV-1 acquisition, is a promising new HIV-1 prevention strategy. We recently demonstrated in the Partners PrEP Study, a randomized, placebo-controlled trial of PrEP among HIV-1 uninfected partners in 4758 African heterosexual HIV-1 serodiscordant couples, that oral emtricitabine/tenofovir (FTC/TDF) PrEP reduced HIV-1 acquisition risk by 75% (p<0.001). However, not all PrEP trials have shown HIV-1 protection; a number of hypotheses have been proposed to explain divergent PrEP trial results in women, primarily adherence to PrEP but also evidence to suggest possible biologic or behavioral interactions between PrEP and hormonal contraception. Whether any potential increase in HIV-1 risk due to contraceptive method could be offset by PrEP use is a critical question for the development of dual protection strategies (i.e., providing protection against HIV-1 and pregnancy), as is whether PrEP and hormonal contraceptives interact in a way that might undermine their HIV- 1 or pregnancy prevention effects. We are uniquely positioned to analyze data and samples from the Partners PrEP Study to inform key questions exploring the interactions of hormonal contraceptive use, PrEP use, and HIV-1 and pregnancy outcomes. Specifically, we will: 1) assess the effect of hormonal contraception on risk of HIV-1 acquisition in women and transmission from women to their male partners, 2) determine whether a) HIV-1 protection by PrEP is diminished in contraceptive users and b) PrEP reduces the pregnancy- prevention effects of contraception, and 3) among HIV-1 uninfected women, measure bias in sexual behavioral reporting for hormonal contraceptive users vs. non-users, which could explain whether increased HIV-1 risk for hormonal users is primarily a biologic or behavioral effect - an important step for prioritizing research and policy responses. The proposed analyses offer an unprecedented opportunity to examine important global public health questions: what is the spectrum of risk associated with use of different contraceptives, can antiretrovirals be used safety for prevention in conjunction with common hormonal contraceptive methods, and can PrEP offset potential increased HIV-1 risk associated with hormonal contraceptive use? The project team has the expertise to address these timely questions with this dataset. The results of the proposed projects will fill critical knowledge gaps that are key to the health of women worldwide and are urgently needed by family planning advocates, HIV-1 prevention scientists, clinicians, and policymakers in order to develop clear messages for women using hormonal contraception and to provide the safest contraceptive options to women with and at-risk for HIV-1.